Propellant-free aerosol formulation for inhalation

ABSTRACT

The present invention relates to propellant-free aerosol formulations for inhalation containing ipratropium bromide and salbutamol.

The present invention relates to propellant-free aerosol formulationsfor inhalation containing ipratropium bromide and salbutamol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to propellant-free solution formulationsfor inhalation which contain the active substances salbutamol,optionally in the form of the pharmacologically acceptable acid additionsalts thereof, and ipratropium bromide and optionally further excipientsin a solvent selected from among water, ethanol and water-ethanolmixtures, while the weight ratio of salbutamol to ipratropium bromide isin the range from 5:1 to 5.5:1.

The solution formulations according to the invention do not contain anyother active substances besides salbutamol and ipratropium bromide.

The weight ratio of salbutamol/ipratropium bromide is based on the ratioby mass of salbutamol contained in the solution formulation toipratropium bromide contained in the solution.

The salbutamol is preferably contained in the formulations according tothe invention in the form of one of the acid addition salts thereof withpharmacologically acceptable acids. Preferred acid addition salts ofsalbutamol are selected from the salts of hydrochloric acid, hydrobromicacid, nitric acid, sulphuric acid and phosphoric acid. Particularlypreferably according to the invention, the salbutamol is used in theformulations according to the invention in the form of the sulphuricacid addition salt thereof. This acid addition salt is optionally alsoreferred to within the scope of the present invention as salbutamolsulphate. The ipratropium bromide may be used in the preparation of theformulations according to the invention in anhydrous form or also in theform of one of its hydrates, preferably in the form of its monohydrate.

The medicament formulations according to the invention contain assolvent pure water, pure ethanol or mixtures of ethanol and water. Ifethanol-water mixtures are used, the percentage content of ethanol bymass in these mixtures is preferably in the range between 5 and 99%ethanol, particularly preferably in the range from 10 to 96% ethanol.Most particularly preferred medicament formulations for the purposes ofthe present invention contain as solvent pure water, pure ethanol orethanol-water mixtures containing between 50 and 92%, particularlypreferably between 69 and 91% ethanol.

Optionally other cosolvents may be used besides ethanol and water. Theyare preferably selected from among the alcohols or ethers, such as forexample isopropanol or tetrahydrofuran. However, according to theinvention preferably no other solvent is used.

Particularly preferred medicament formulations according to theinvention contain only water as solvent.

Normally, the formulations according to the invention containpharmacologically acceptable acids to adjust the pH. The pH of theformulation according to the invention is preferably in the range from3.0 and 4.0, preferably between 3.1 and 3.7, particularly preferablybetween 3.3 and 3.5 according to the invention. Particularly preferredsolution formulations have a pH of 3.4.

Pharmacologically acceptable acids used to adjust the pH may beinorganic acids or organic acids. Examples of preferred inorganic acidsare selected from the group consisting of hydrochloric acid, hydrobromicacid, nitric acid, sulphuric acid and phosphoric acid. Examples ofparticularly suitable organic acids are selected from the groupconsisting of ascorbic acid, citric acid, malic acid, tartaric acid,maleic acid, succinic acid, fumaric acid, acetic acid, formic acid andpropionic acid. Preferred inorganic acids are hydrochloric acid andsulphuric acid, of which hydrochloric acid is particularly preferredaccording to the invention. Of the organic acids, ascorbic acid, fumaricacid and citric acid are preferred, while citric acid is particularlypreferred according to the invention. If desired, mixtures of theabovementioned acids may also be used, particularly in the case of acidswhich have other properties in addition to their acidifying properties,e.g. those which act as flavourings or antioxidants, such as for examplecitric acid or ascorbic acid.

If desired, pharmacologically acceptable bases may be used to titratethe pH precisely. Suitable bases include for example alkali metalhydroxides and alkali metal carbonates. The preferred alkali metal ionis sodium. If bases of this kind are used, care must be taken to ensurethat the resulting salts, which are then contained in the finishedpharmaceutical formulation, are pharmacologically compatible with theabovementioned acid.

Examples of further excipients, which may optionally also be present inthe solutions according to the invention in addition to the activesubstances salbutamol and ipratropium bromide, are particularly andpreferably preservatives and complexing agents according to theinvention.

By complexing agents are meant within the scope of the present inventionmolecules which are capable of entering into complex bonds. Preferably,these compounds should have the effect of complexing cations, mostpreferably metal cations. The formulations according to the inventionpreferably contain editic acid (EDTA) or one of the known salts thereof,e.g. sodium EDTA or disodium EDTA. Preferably, disodium edetate is used,optionally in the form of its hydrates, particularly preferably in theform of its dihydrate. If disodium edetate is used as complexing agentwithin the scope of the formulations according to the invention, thecontent of disodium edetate is preferably in the range from 0 to 100 mgpro 10 g, particularly preferably in the range from 5 to 70 mg per 100 gof the formulation according to the invention. Preferably, theformulations according to the invention contain a complexing agent,particularly preferably disodium edetate in an amount of about 40 to 60mg per 100 g, particularly preferably about 45 to 55 mg per 100 g,particularly preferably 50 mg per 100 g of the formulation according tothe invention. Of equal importance according to the invention areformulations which contain the complexing agent in an amount of about 7to 12 mg per 100 g, particularly preferably about 10 mg per 100 g of theformulation according to the invention.

Also of equal importance according to the invention are formulationswhich contain the complexing agent in an amount of about 3 to 7 mg per100 g, particularly preferably about 5 mg per 100 g of the formulationaccording to the invention.

Preservatives may be used to protect the formulation from contaminationwith pathogens. Suitable preservatives are those which are known in theart, particularly benzalkonium chloride, cetyl pyridinium chloride orbenzoic acid or benzoates such as sodium benzoate in the concentrationsknown from the prior art. Preferably benzalkonium chloride is added tothe formulation according to the invention. The amount of benzalkoniumchloride is between 1 mg and 50 mg per 100 g formulation, preferablyabout 2 to 15 mg per 100 g, particularly preferably about 3 to 12 mg per100 g, particularly preferably about 10 mg per 100 g of the formulationaccording to the invention. Benzalkonium chloride may also be usedaccording to the invention in admixture with other preservatives.

In the formulations according to the invention ipratropium bromide isusually present in an amount of from 125-200 mg per 100 g solution.Preferably the formulations according to the invention contain theactive substance ipratropium bromide in an amount of 150-190 mg per 10 gsolution, particularly preferably in an amount of 160-180 mg per 100 gsolution. The skilled man will easily be able to calculate from thesefigures the corresponding amounts of ipratropium bromide-monohydratewhich are particularly preferably used according to the invention.

Particularly preferred formulations according to the invention containbesides the above-mentioned amounts of ipratropium bromide an amount ofsalbutamol such that the weight ratio of salbutamol to ipratropiumbromide is in the range from 5.1:1 to 5.4:1. In particularly preferredformulations according to the invention the weight ratio of salbutamolto ipratropium bromide is in the range from 5.2:1 to 5.3:1.

Particularly preferred formulations according to the invention contain160-190 mg, preferably 170 to 180 mg ipratropium bromide-monohydrate and900-1200 mg, preferably 1000-1100 mg salbutamol sulphate per 100 gsolution.

In another aspect the present invention relates to the use of theabove-mentioned medicament formulations according to the invention forpreparing a medicament for the treatment of respiratory complaintsselected from the group comprising obstructive pulmonary diseases ofvarious origins, pulmonary emphysema of various origins, restrictivepulmonary diseases, interstitial pulmonary diseases, cystic fibrosis,bronchitis of various origins, bronchiectasis, ARDS (adult respiratorydistress syndrome) and all forms of pulmonary oedema.

Preferably, the medicament formulations according to the invention areused to prepare a medicament for the treatment of obstructive pulmonarydiseases selected from the group consisting of bronchial asthma,paediatric asthma, severe asthma, acute asthma attacks, chronicbronchitis and chronic obstructive pulmonary disease (COPD), while theiruse for preparing a medicament for the treatment of bronchial asthma orCOPD is particularly preferred according to the invention.

Also preferably, the medicament formulations according to the inventionare used to prepare a medicament for the treatment of pulmonaryemphysema which has its origins in COPD (chronic obstructive pulmonarydisease) or α1-proteinase inhibitor deficiency.

Also preferably, the medicament formulations according to the inventionare used to prepare a medicament for the treatment of restrictivepulmonary diseases selected from among allergic alveolitis, restrictivepulmonary diseases triggered by work-related noxious substances, such asasbestosis or silicosis, and restriction caused by lung tumours, such asfor example lymphangiosis carcinomatosa, bronchoalveolar carcinoma andlymphomas.

Also preferably, the medicament formulations according to the inventionare used to prepare a medicament for the treatment of interstitialpulmonary diseases selected from among pneumonia caused by infections,such as for example infection by viruses, bacteria, fungi, protozoa,helminths or other pathogens, pneumonitis caused by various factors,such as for example aspiration and left heart insufficiency,radiation-induced pneumonitis or fibrosis, collagenoses, such as forexample lupus erythematodes, systemic scleroderma or sarcoidosis,granulomatoses, such as for example Boeck's disease, idiopathicinterstitial pneumonia or idiopathic pulmonary fibrosis (IPF).

Also preferably, the medicament formulations according to the inventionare used to prepare a medicament for the treatment of cystic fibrosis ormucoviscidosis.

Also preferably, the medicament formulations according to the inventionare used to prepare a medicament for the treatment of bronchitis, suchas for example bronchitis caused by bacterial or viral infection,allergic bronchitis and toxic bronchitis.

Also preferably, the medicament formulations according to the inventionare used to prepare a medicament for the treatment of bronchiectasis.

Also preferably, the medicament formulations according to the inventionare used to prepare a medicament for the treatment of ARDS (adultrespiratory distress syndrome).

Also preferably, the medicament formulations according to the inventionare used to prepare a medicament for the treatment of pulmonary oedema,for example toxic pulmonary oedema after aspiration or inhalation oftoxic substances and foreign substances.

Particularly preferably the present invention relates to the use of themedicament formulations according to the invention for preparing amedicament for the treatment of asthma or COPD. Also of particularimportance is the above-mentioned use for preparing a medicament fortreating inflammatory and obstructive respiratory complaints, mostparticularly asthma or COPD, several times a day, preferably three tofour times a day.

The present invention also relates to a process for the treatment of theabove-mentioned diseases, characterised in that one or more of theabove-mentioned medicament formulations according to the invention areadministered in therapeutically effective amounts.

The present invention further relates to the use of the above-mentionedmedicament formulations for preparing a medicament for the treatment ofone of the above-mentioned diseases, particularly asthma or COPD,characterised in that about 5 to 25 μl (microlitres), preferably about 7to 20 μl of the solutions according to the invention are administeredper dose of medicament. It is particularly preferable to use theabove-mentioned medicament formulations for preparing a medicament forthe treatment of one of the above-mentioned diseases, particularlyasthma or COPD, characterised in that about 10 to 13 μl of the solutionsaccording to the invention are administered per dose of medicament.

It is particularly preferable to use the above-mentioned medicamentformulations for preparing a medicament for the treatment of one of theabove-mentioned diseases, particularly asthma or COPD, characterised inthat the above-mentioned quantities of solution once or twice per doseare administered, while the administration of a single dose isparticularly preferred according to the invention.

It is particularly preferable to use the above-mentioned medicamentformulations for preparing a medicament for the treatment of one of theabove-mentioned diseases, particularly asthma or COPD, characterised inthat the above-mentioned administration of medicament occurring once ortwice, preferably once per dose, is given at least once a day,preferably at least twice a day, particularly preferably three- to fourtimes a day.

The present invention further relates to a method of treating one of theabove-mentioned diseases, particularly asthma or COPD, characterised inthat about 5 to 25 μl (microlitres), preferably about 7 to 20 μl of thesolutions according to the invention are administered per dose ofmedicament. Particularly preferred is a method of treating one of theabove-mentioned diseases, particularly asthma or COPD, wherein about 10to 13 μl of the solutions according to the invention are administeredper dose of medicament.

Also particularly preferred is a method of treating one of theabove-mentioned diseases, particularly asthma or COPD, characterised inthat the above-mentioned quantities of solution are administered once ortwice per dose, while it is particularly preferable to administer onlyone quantity per dose, according to the invention.

Also particularly preferred is a method of treating one of theabove-mentioned diseases, particularly asthma or COPD, characterised inthat the above-mentioned administration of medicament occurring once ortwice, preferably once per dose, is given at least once a day,preferably at least twice a day, particularly preferably three to fourtimes a day.

The formulations according to the invention may be inhaled orally ornasally. To achieve an optimum distribution of the active substances inthe lungs it is advisable to use a liquid formulation free frompropellant gases which is delivered using inhalers suitable for thispurpose. A formulation of this kind may be administered by both oral andnasal inhalation. Those inhalers which are capable of nebulising a smallamount of a liquid formulation in the dosage needed for therapeuticpurposes within a few seconds into an aerosol suitable for therapeuticinhalation are particularly suitable.

An apparatus of this kind for the propellant-free administration of ametered amount of a liquid pharmaceutical composition for inhalation isdescribed in detail for example in International Patent Application WO91/14468 and also in WO 97/12687, cf FIGS. 6a and 6b and theaccompanying description. In a nebuliser of this kind a pharmaceuticalsolution is converted by means of a high pressure of up to 600 bar intoan aerosol destined for the lungs, which is sprayed. Within the scope ofthe present specification reference is expressly made to the entirecontents of the literature mentioned above.

In inhalers of this kind the formulations of solutions are stored in areservoir. It is essential that the active substance formulations usedare sufficiently stable when stored and at the same time are such thatthey can be administered directly, if possible without any furtherhandling, in accordance with their medical purpose. Moreover, they mustnot contain any ingredients which might interact with the inhaler insuch a way as to damage the inhaler or the pharmaceutical quality of thesolution or of the aerosol produced.

To nebulise the solution a special nozzle is used as described forexample in WO 94/07607 or WO 99/16530. Reference is expressly made hereto both these publications.

The aim of the present invention is to provide an aqueous, ethanolic oraqueous-ethanolic formulation of the compound of formula 1 which meetsthe high standards needed in order to be able to achieve optimumnebulisation of a solution using the inhalers mentioned hereinbefore.The active substance formulations according to the invention must be ofsufficiently high pharmaceutical quality, i.e. they should bepharmaceutically stable over a storage time of some years, preferably atleast one year, more preferably two years. These propellant-freeformulations must also be capable of being nebulised under pressureusing an inhaler, the composition delivered by the aerosol producedfalling reproducibly within a specified range.

The medicament formulations according to the invention are preferablyused in an inhaler of the kind described hereinbefore in order toproduce the propellant-free aerosols according to the invention. At thispoint we should once again expressly mention the patent documentsdescribed hereinbefore, the contents of which are hereby incorporated byreference.

As described at the beginning, a further developed embodiment of thepreferred inhaler is disclosed in WO 97/12687 (see in particular FIGS.6a and 6b and the associated parts of the description). This nebuliser(Respimat®) can advantageously be used to produce the inhalable aerosolsaccording to the invention. Because of its cylindrical shape and handysize of less than 9 to 15 cm long and 2 to 4 cm wide, the device can becarried anywhere by the patient. The nebuliser sprays a defined volumeof the medicament formulation out through small nozzles at highpressures, so as to produce inhalable aerosols.

The preferred atomiser essentially consists of an upper housing part, apump housing, a nozzle, a locking clamp, a spring housing, a spring anda storage container, characterised by

-   -   a pump housing fixed in the upper housing part and carrying at        one end a nozzle body with the nozzle or nozzle arrangement,    -   a hollow piston with valve body,    -   a power take-off flange in which the hollow body is fixed and        which is located in the upper housing part,    -   a locking clamping mechanism located in the upper housing part,    -   a spring housing with the spring located therein, which is        rotatably mounted on the upper housing part by means of a rotary        bearing,    -   a lower housing part which is fitted onto the spring housing in        the axial direction.

The hollow piston with valve body corresponds to a device disclosed inWO 97/12687. It projects partially into the cylinder of the pump housingand is disposed to be axially movable in the cylinder. Reference is madeparticularly to FIGS. 1-4—especially FIG. 3—and the associated parts ofthe description. At the moment of release of the spring the hollowpiston with valve body exerts, at its high pressure end, a pressure of 5to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to600 bar) on the fluid, the measured amount of active substance solution.Volumes of 10 to 50 microlitres are preferred, volumes of 10 to 20microlitres are more preferable, whilst a volume of 15 microlitres peractuation is particularly preferred.

The valve body is preferably mounted at the end of the hollow pistonwhich faces the nozzle body.

The nozzle in the nozzle body is preferably microstructured, i.e.manufactured by micro-engineering. Microstructured nozzle bodies aredisclosed for example in WO-94/07607 and in WO 99/16530; reference ishereby made to the contents thereof, especially FIG. 1 of WO-94/07607and the associated description.

The nozzle body consists for example of two sheets of glass and/orsilicon securely fixed together, at least one of which has one or moremicrostructured channels which connect the nozzle inlet end to thenozzle outlet end. At the nozzle outlet end there is at least one roundor non-round opening 2 to 10 microns deep and 5 to 15 microns wide, thedepth preferably being 4.5 to 6.5 microns and the length being 7 to 9microns.

If there is a plurality of nozzle openings, preferably two, thedirections of spraying of the nozzles in the nozzle body may runparallel to each other or may be inclined relative to one another in thedirection of the nozzle opening. In the case of a nozzle body having atleast two nozzle openings at the outlet end, the directions of sprayingmay be inclined relative to one another at an angle of 20 degrees to 160degrees, preferably at an angle of 60 to 150 degrees, most preferably 80to 100°.

The nozzle openings are preferably arranged at a spacing of 10 to 200microns, more preferably at a spacing of 10 to 100 microns, still morepreferably 30 to 70 microns. A spacing of 50 microns is most preferred.

The directions of spraying therefore meet in the region of the nozzleopenings.

As already mentioned, the liquid pharmaceutical preparation hits thenozzle body at an entry pressure of up to 600 bar, preferably 200 to 300bar and is atomised through the nozzle openings into an inhalableaerosol. The preferred particle sizes of the aerosol are up to 20microns, preferably 3 to 10 microns.

The locking clamping mechanism contains a spring, preferably acylindrical helical compression spring as a store for the mechanicalenergy. The spring acts on the power take-off flange as a spring memberthe movement of which is determined by the position of a locking member.The travel of the power take-off flange is precisely limited by an upperstop and a lower stop. The spring is preferably tensioned via astepping-up gear, e.g. A helical sliding gear, by an external torquewhich is generated when the upper housing part is turned relative to thespring housing in the lower housing part. In this case, the upperhousing part and the power take-off flange contain a single- ormulti-speed spline gear.

The locking member with the engaging locking surfaces is arranged in anannular configuration around the power take-off flange. It consists forexample of a ring of plastics or metal which is inherently radiallyelastically deformable. The ring is arranged in a plane perpendicular tothe axis of the atomiser. After the locking of the spring, the lockingsurfaces of the locking member slide into the path of the power take-offflange and prevent the spring from being released. The locking member isactuated by means of a button. The actuating button is connected orcoupled to the locking member. In order to actuate the locking clampingmechanism the actuating button is moved parallel to the annular plane,preferably into the atomiser, and the deformable ring is therebydeformed in the annular plane. Details of the construction of thelocking clamping mechanism are described in WO 97/20590.

The lower housing part is pushed axially over the spring housing andcovers the bearing, the drive for the spindle and the storage containerfor the fluid.

When the atomiser is operated, the upper part of the housing is rotatedrelative to the lower part, the lower part taking the spring housingwith it. The spring meanwhile is compressed and biased by means of thehelical sliding gear, and the clamping mechanism engages automatically.The angle of rotation is preferably a whole-number fraction of 360degrees, e.g. 180 degrees. At the same time as the spring is tensioned,the power take-off component in the upper housing part is moved along bya given amount, the hollow piston is pulled back inside the cylinder inthe pump housing, as a result of which some of the fluid from thestorage container is sucked into the high pressure chamber in front ofthe nozzle.

If desired, a plurality of replaceable storage containers containing thefluid to be atomised can be inserted in the atomiser one after anotherand then used. The storage container contains the aqueous aerosolpreparation according to the invention.

The atomising process is initiated by gently pressing the actuatingbutton. The clamping mechanism then opens the way for the power take-offcomponent. The biased spring pushes the piston into the cylinder in thepump housing. The fluid emerges from the nozzle of the atomiser in theform of a spray.

Further details of the construction are disclosed in PCT applications WO97/12683 and WO 97/20590, to which reference is hereby made.

The components of the atomiser (nebuliser) are made of a materialsuitable for their function. The housing of the atomiser and—if thefunction allows—other parts as well are preferably made of plastics,e.g. by injection moulding. For medical applications, physiologicallyacceptable materials are used.

FIGS. 6a/b of WO 97/12687 show the Respimat® nebuliser with which theaqueous aerosol preparations according to the invention canadvantageously be inhaled.

FIG. 6a shows a longitudinal section through the atomiser with thespring under tension, FIG. 6b shows a longitudinal section through theatomiser with the spring released.

The upper housing part (51) contains the pump housing (52), on the endof which is mounted the holder (53) for the atomiser nozzle. In theholder is the nozzle body (54) and a filter (55). The hollow piston (57)fixed in the power take-off flange (56) of the locking clampingmechanism projects partly into the cylinder of the pump housing. At itsend the hollow piston carries the valve body (58). The hollow piston issealed off by the gasket (59). Inside the upper housing part is the stop(60) on which the power take-off flange rests when the spring isrelaxed. Located on the power take-off flange is the stop (61) on whichthe power take-off flange rests when the spring is under tension. Afterthe tensioning of the spring, the locking member (62) slides between thestop (61) and a support (63) in the upper housing part. The actuatingbutton (64) is connected to the locking member. The upper housing partends in the mouthpiece (65) and is closed off by the removableprotective cap (66).

The spring housing (67) with compression spring (68) is rotatablymounted on the upper housing part by means of the snap-fit lugs (69) androtary bearings. The lower housing part (70) is pushed over the springhousing. Inside the spring housing is the replaceable storage container(71) for the fluid (72) which is to be atomised. The storage containeris closed off by the stopper (73), through which the hollow pistonprojects into the storage container and dips its end into the fluid(supply of active substance solution).

The spindle (74) for the mechanical counter is mounted on the outside ofthe spring housing. The drive pinion (75) is located at the end of thespindle facing the upper housing part. On the spindle is the slider(76).

The nebuliser described above is suitable for nebulising the aerosolpreparations according to the invention to form an aerosol suitable forinhalation.

If the formulation according to the invention is nebulised using themethod described above (Respimat®), the mass expelled, in at least 97%,preferably at least 98% of all the actuations of the inhaler (puffs),should correspond to a defined quantity with a range of tolerance of notmore than 25%, preferably 20% of this quantity. Preferably, between 5and 30 mg, more preferably between 5 and 20 mg of formulation aredelivered as a defined mass per puff.

The formulation according to the invention can also be nebulised usinginhalers other than those described above, for example jet-streaminhalers.

The present invention also relates to an inhalation kit consisting ofone of the medicament preparations according to the invention describedabove and an inhaler suitable for nebulising this pharmaceuticalpreparation.

The present invention preferably relates to an inhalation kit consistingof one of the medicament preparations according to the inventiondescribed above and the Respimat® inhaler described above.

The examples of formulations given below serve as illustrations withoutrestricting the subject matter of the present invention to thecompositions shown by way of example.

The percentages given are percent by mass (w/w) in each case.

A) Preparation of the Formulations

Pure water is placed in a container and to this are added, withstirring, at ambient temperature, ipratropium bromide monohydrate,salbutamol sulphate, benzalkonium chloride (anhydrous) and disodiumedetate-dihydrate. The quantities of ingredients used in each case areindicated by the formulation ingredients illustrated below. After allthe ingredients have dissolved and water has been added if necessary toobtain the specified concentrations, the solution obtained is adjustedto a pH of 3.4 with 1N aqueous hydrochloric acid.

B) Examples of formulations: In the examples of formulations below, BACdenotes benzalkonium chloride and EDTA denotes disodiumedetate-dihydrate. The Examples were adjusted to a pH of 3.4 with 1Naqueous hydrochloric acid.

ipratropium BAC EDTA bromide- Exam- [mg/ [mg/ monohydrate salbutamolpurified ple 100 g] 100 g] [g/100 g] [g/100 g] water 1 10 50 0.1750.877¹⁾ ad 100 g 2 10 10 0.175 0.877¹⁾ ad 100 g 3 10 5 0.175 0.877¹⁾ ad100 g ¹⁾corresponds to 1.057 g salbutamol sulphate per 100 g solution;

C) Use in the Respimat: if the formulations specified under B) areadministered using the Respimat® inhaler, each puff (about 11.4 μlvolume) delivers the quantities of formulation ingredients specifiedbelow to the patient.

ipratropium BAC EDTA bromide- Exam- [mg/ [mg/ monohydrate salbutamolpurified ple Hub] Hub] [mg/Hub] [mg/Hub] water 1 0.00114 0.0057 0.020.10¹⁾ ad 11.4 mg 2 0.00114 0.00114 0.02 0.10¹⁾ ad 11.4 mg 3 0.001140.00057 0.02 0.10¹⁾ ad 11.4 mg ¹⁾corresponds to 0.1205 mg salbutamolsulphate per puff;

1. A propellant-free solution formulation for inhalation which containthe active substances salbutamol, optionally in the form of thepharmacologically acceptable acid addition salts thereof, andipratropium bromide and optionally further excipients, in a solventselected from among water, ethanol and water-ethanol mixtures, theweight ratio of salbutamol to ipratropium bromide being in the rangefrom 5:1 to 5.5:1 and the solution formulation containing no otheractive substances.
 2. The propellant-free solution formulation accordingto claim 1, wherein the salbutamol is present in the form of one of thepharmacologically acceptable acid addition salts thereof with an acidselected from among hydrochloric acid, hydrobromic acid, nitric acid,sulphuric acid and phosphoric acid.
 3. The propellant-free solutionformulation according to claim 1, wherein the solvent is water.
 4. Thepropellant-free solution formulation according to claim 1, wherein thepH of the formulation is in the range from 3.0 and 4.0.
 5. Thepropellant-free solution formulation according to claim 4, wherein thepH is adjusted using inorganic or organic acids.
 6. The propellant-freesolution formulation according to claim 5, wherein it contains asfurther constituents one or more compounds selected from among thepreservatives and complexing agents.
 7. The propellant-free solutionformulation according to claim 6, wherein the complexing agent is editicacid (EDTA) or one of the known salts thereof.
 8. The propellant-freesolution formulation according to claim 6, wherein the preservative isbenzalkonium chloride, cetylpyridinium chloride, benzoic acid or a saltof benzoic acid.
 9. A propellant-free solution formulation according toclaim 2, wherein the acid is sulphuric acid.
 10. A propellant-freesolution formulation according to claim 1, wherein the pH of theformulation is in the range from 3.1 and 3.7.